This invention relates generally to the field of chemistry, and in particular to solid phase chemistry. More specifically, in one aspect the invention relates to solid supports used in solid phase chemistry. In another aspect, the invention relates to polymer based solid supports that may be used to facilitate drug delivery.
Traditionally, experimental chemistries have been performed in solution where various chemicals are reacted while in solution phase. For example, a chemist may desire to perform an experiment to react chemical A with a chemical B to produce a reaction product. To do so using solution phase techniques, the chemist may combine chemical A with chemical B in a solution using a given set of reaction conditions. To increase the rate of the reaction and to insure completion of the chemistry, i.e., maximum conversion of A, an excessive amount of chemical B may be used. However, once the reaction is complete, the excess of chemical B needs to be separated from the product. Such a process can be both difficult and time consuming.
As an alternative to solution phase chemistries, solid phase chemistries have been developed which use solid supports to serve as a xe2x80x9chandlexe2x80x9d during the synthesis process. Examples of such solid supports are described generally in Anthony W. Czarnick et al., xe2x80x9cA Practical Guide to Combinatorial Chemistry,xe2x80x9d American Chemical Society 1997, the complete disclosure of which is herein incorporated by reference. By using, for example, polystyrene beads, chemical A may be linked to the bead, and an excess of chemical B may be supplied to the bead to drive the chemical reaction at a faster rate and to completion. Following the reaction, the product P may easily be separated from any excess of chemical B since P is physically linked to the bead. Techniques for performing combinatorial chemistry are described generally in Barry A. Bunin, xe2x80x9cThe Combinatorial Index,xe2x80x9d Academic Press 1998, the complete disclosure of which is herein incorporated by reference.
However, use of such beads in solid phase chemistries presents other challenges. For example, once chemical B has reacted to form a product, the product needs to be removed from the bead. This may be accomplished, for example, by placing the bead into a reagent that is selected to cleave the product from the bead. Once cleaved, the product then needs to be removed from the bead and the reagent.
An example of such a process is illustrated in FIG. 1. Shown in FIG. 1 is a solid support 10 that comprises a series of polymer chains 12 that are linked together by cross links 14. The polymer chains 12 also include cleavable links 16 where chemistries are performed. As shown in FIG. 1, chemical synthesis is performed to produce chemical compounds 18 that are coupled to links 16. Compounds 18 are then cleaved from links 18 to remove the compounds 18 from the solid support 10. Following cleavage, the removed compounds 18 are filtered with a filter 20 to separate the compounds from the solid support.
As illustrated in FIG. 1, some of the compounds 18 remain trapped within the solid support. As a result the compounds that remain within solid support 10 are unavailable for use in subsequent procedures. Removal of the compound or product may be challenging for a variety of reasons. For example, transfer of the cleaved product from within the bead to the bulk solution may occur by diffusion. This may introduce a loss of the product if the product has an affinity for the bead and experiences absorption effects during diffusion. As another example, the cleaved product may precipitate within the bead, thereby hindering its removal. At a minimum, an amount of product is left trapped within the interior or the bead in an amount proportional to the solvent volume inside the bead to the volume exterior to the bead.
Hence, the invention relates to the use of solid supports that are configured to facilitate chemical reactions and to efficiently remove chemical products from the solid supports following synthesis. The invention also relates to the use of such solid supports for drug delivery.
The invention provides solid supports and methods for their construction and use to facilitate the performance of a chemical process or a series of chemical processes or for drug delivery. According to one method, a cross linked solid support is provided having a first set of cleavable links that are present within the cross links and a second set of cleavable links that provide sites on which to carry out chemistry. A first chemical is coupled to the chemistry sites and is then reacted with a second chemical to produce a reaction product. The links are then cleaved to break the cross links and to cleave the reaction product from the solid support. In this way, the un-cross linked solid support is permitted to separate to facilitate removal of the reaction product from the solid support. Conveniently, the first and second cleavable links may be cleaved simultaneously under the same or similar conditions, and may comprise the same or a different chemical entity. Alternatively, the first and second links may be independently cleavable, i.e. orthogonally cleavable, under conditions specific to each link.
Following cleavage, the cleaved reaction product may then be separated from the un-cross linked solid support. For example, the cleaved reaction product may be filtered from the un-cross linked solid support with a filter or a semi-permeable membrane.
In some cases, the solid support may be provided with a third set of cleavable links that are present within the cross links and that are orthogonally cleavable relative to the first and/or second set of links. Such a configuration of the solid support permits the third set of cross links to be cleaved while the first and/or second set of links (which are present within the cross links of the solid support and provide the chemistry sites for the attachment of chemicals or chemical products) remain intact. For example, the third set of cross links may be cleaved prior to the first set of links to partially open the solid support to facilitate the entry of materials into the solid support when performing a chemical step or a series of chemical steps. As another example, the third set of cross links may be cleaved to facilitate the performance of an assay, such as a direct binding assay. As a further example, the third set of links may be cleaved to allow access to the products of a reaction by an enzyme to determine if conversion of the reaction product by the enzyme occurs.
In one aspect, the solid support may be constructed of a series of polymer chains that are cross linked by bi-functional reagents containing the cleavable links. In this way, cleavage of the links unlinks the polymer chains.
The invention further provides a solid support for use in performing chemical synthesis. The solid support comprises a series of polymer chains and a set of cleavable links both within the cross links crosslinking the polymer chains and providing chemistry sites. In this way, cleavage of the links both un-cross links the polymer chains and removes any chemicals or chemical products that were previously attached to the chemistry sites. Examples of polymer chains that may be used to construct the solid supports include polymerized styrene, acrylic monomers, ether monomers, and the like.
In one aspect, the solid supports may further include another set of cleavable links within the cross links that are orthogonally cleavable relative to the other set of cleavable links within the cross links. In this way, one set of links may be cleaved while the other set remain intact.
The invention further provides a method for constructing a solid support. According to the method, a set of components are combined in a mixture. The components include a base set of monomers, a set of functional monomers for post polymerization modification, and a set of bivalent cross linking monomers which contain a cleavable link. The components are polymerized to form a plurality of solid supports that each comprise a series of polymer chains and a set of cross links containing cleavable links cross linking the polymer chains. In a further step, a plurality of chemistry site links may be attached to the polymer chains, with the chemistry site links being cleavable under the same conditions as are those within the cross links.
In another embodiment, a solid support for performing chemical synthesis comprises a grafting surface and a set of cleavable links that are attached to the surface. A series of chemical chains on which to attach chemistry links are then attached to the cleavable links.